Re-engineering of the Duocarmycin Structural Architecture Enables Bioprecursor Development Targeting CYP1A1 and CYP2W1 for Biological Activity

Sheldrake, Helen M.; Travica, Sandra; Johansson, Inger; Loadman, Paul M.; Sutherland, Mark; Elsalem, Lina; Illingworth, Nicola A.; Cresswell, Alexander J.; Reuillon, Tristan; Shnyder, Steve D.; Mkrtchian, Souren; Searcey, Mark; Ingelman‐Sundberg, Magnus; Patterson, Laurence H.; Pors, Klaus

doi:10.1021/jm4000209

Cited by 34 publications

(44 citation statements)

References 23 publications

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“…Accordingly, some anticancer compounds have been developed, which are selectively bioactivated by CYP2W1 into potent cytotoxic drugs, such as AQ4N [27], 5F-203 and GW-610 [12], and duocarmycin bioprecursors [28], [29]. This approach has recently been studied both in vitro and in vivo demonstrating that the duocarmycin analog ICT2706 is converted by tumor cells into a potent cytotoxin inhibiting the growth of human colon cancer xenografts [28], [29]. Of particular interest is the observation of a bystander effect affecting adjacent cells not expressing CYP2W1 by the toxins generated in CYP2W1 expressing cells, suggesting a relevant therapeutic potential of an anti-tumor strategy exploiting bioactivation by CYP2W1.…”

Section: Discussionmentioning

confidence: 99%

CYP2W1 Is Highly Expressed in Adrenal Glands and Is Positively Associated with the Response to Mitotane in Adrenocortical Carcinoma

Ronchi¹,

Sbiera²,

Volante

et al. 2014

PLoS ONE

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BackgroundAdrenocortical tumors comprise frequent adenomas (ACA) and rare carcinomas (ACC). Human cytochrome P450 2W1 (CYP2W1) is highly expressed in some cancers holding the potential to activate certain drugs into tumor cytotoxins.ObjectiveTo investigate the CYP2W1 expression in adrenal samples and its relationship with clinical outcome in ACC.Material and MethodsCYP2W1 expression was investigated by qRT-PCR in 13 normal adrenal glands, 32 ACA, 25 ACC, and 9 different non-adrenal normal tissue samples and by immunohistochemistry in 352 specimens (23 normal adrenal glands, 33 ACA, 239 ACC, 67 non-adrenal normal or neoplastic samples).Results CYP2W1 mRNA expression was absent/low in normal non-adrenal tissues, but high in normal and neoplastic adrenal glands (all P<0.01 vs non-adrenal normal tissues). Accordingly, CYP2W1 immunoreactivity was absent/low (H-score 0–1) in 72% of non-adrenal normal tissues, but high (H-score 2–3) in 44% of non-adrenal cancers, in 65% of normal adrenal glands, in 62% of ACAs and in 50% of ACCs (all P<0.001 vs non-adrenal normal tissues), being significantly increased in steroid-secreting compared to non-secreting tumors. In ACC patients treated with mitotane only, high CYP2W1 immunoreactivity adjusted for ENSAT stage was associated with longer overall survival and time to progression (P<0.05 and P<0.01, respectively), and with a better response to therapy both as palliative (response/stable disease in 42% vs 6%, P<0.01) or adjuvant option (absence of disease recurrence in 69% vs 45%, P<0.01).ConclusionCYP2W1 is highly expressed in both normal and neoplastic adrenal glands making it a promising tool for targeted therapy in ACC. Furthermore, CYP2W1 may represent a new predictive marker for the response to mitotane treatment.

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Section: Discussionmentioning

confidence: 99%

CYP2W1 Is Highly Expressed in Adrenal Glands and Is Positively Associated with the Response to Mitotane in Adrenocortical Carcinoma

Ronchi¹,

Sbiera²,

Volante

et al. 2014

PLoS ONE

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“…Certain isoforms, notably CYP1A1, 1B1 and 3A4 are identified as highly expressed in certain tumours 10 indicating the value of truncated azinomycin analogues as potential bioprecursors with chemotherapeutic efficacy. We have demonstrated proof of principle with bioprecursors of the duocarmycin natural products targeting CYP1A1 19,20 and 2W1 14,21 enzymes. Uniquely, we have demonstrated that CYP selective bioactivation in vivo can be obtained with no overt toxicity to normal tissues including the liver.…”

Section: Discussionmentioning

confidence: 97%

Probing cytochrome P450-mediated activation with a truncated azinomycin analogue

et al. 2015

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YesA deactivated alkene precursor (IC50=81 mu M) to the azinomycin epoxide natural product can be bioactivated by several cytochromes P450 (CYP) to generate antiproliferative metabolites with increased potency (IC50=1-30 mu M) in CHOwt cells. CYP1A1 and 3A4 were shown to generate exclusively the unnatural and the natural-configured azinomycin epoxide diastereoisomer respectively, while CYP1B1 produced both epoxides in a 3:1 mixture. The antiproliferative activity is linked to DNA damage as demonstrated using the comet assay

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“…Indeed, chemosensitivity screens using a panel of cell lines including HEK293 and SW480 stably expressing CYP2W1 (SW480-CYP2W1) identified several chloromethylindolines as substrates for these enzymes, where two compounds, designated ICT2705 and ICT2706 demonstrated very high affinity for activation by CYP2W1 (EC 50 ¼ 0.5 and 0.3 lM correspondingly). The LC/MS analysis of ICT2706 metabolism in the CYP2W1 expressing cells identified a specific metabolic product (MW 363.2, m/z 364.2), consistent with a hydroxylated derivative of ICT2706 (Sheldrake et al, 2013) (Figure 3). …”

Section: Cyp2w1 As a Target For Colon Cancer Therapymentioning

confidence: 88%

“…It also appeared that the cytotoxic metabolite of chloromethylindolines can be transferred from one tumor cell to others in close proximity, thus indicating a bystander propagating effect (Sheldrake et al, 2013;Travica et al, 2013).…”

Section: Cyp2w1 As a Target For Colon Cancer Therapymentioning

confidence: 99%

The CYP2W1 enzyme: regulation, properties and activation of prodrugs

Guo

Johansson

Mkrtchian

et al. 2016

Drug Metabolism Reviews

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CYP2W1 is expressed in the course of development of the gastrointestinal tract, silenced after birth in intestine and colon by epigenetic modifications, but activated following demethylation in colorectal cancer (CRC). The expression levels in CRC positively correlate with the degree of malignancy, are higher in metastases and are predictive of colon cancer survival. The CYP2W1 transcripts have been detected also in hepatocellular carcinoma, adrenocortical carcinoma, childhood rhabdomyosarcoma and breast cancer; however, here the protein expression remains to be confirmed. The CYP2W1 enzyme has an inverted orientation in the endoplasmic reticulum membrane, as compared to other cytochrome P450s and its immediate electron donor is unknown. Several lipid ligands have been proposed as endogenous substrates, among which retinol derivatives appear to have the highest affinities. However, the role of CYP2W1 in the endogenous and tumor localized metabolism of retinol derivatives has yet to be clarified. Indolines constitute high affinity exogenous compounds and specific chloromethylindolines have been shown to be activated by CYP2W1 into cytotoxic products in vitro and also in vivo, inhibiting the growth of human colon tumors in a mouse xenograft model. The CRC specific localization of CYP2W1 and its effective prodrug activation makes it a very promising target for future development of cancer therapeutics.

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Re-engineering of the Duocarmycin Structural Architecture Enables Bioprecursor Development Targeting CYP1A1 and CYP2W1 for Biological Activity

Cited by 34 publications

References 23 publications

CYP2W1 Is Highly Expressed in Adrenal Glands and Is Positively Associated with the Response to Mitotane in Adrenocortical Carcinoma

CYP2W1 Is Highly Expressed in Adrenal Glands and Is Positively Associated with the Response to Mitotane in Adrenocortical Carcinoma

Probing cytochrome P450-mediated activation with a truncated azinomycin analogue

The CYP2W1 enzyme: regulation, properties and activation of prodrugs

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